Comparative Effectiveness of Drug Therapy for Rheumatoid Arthritis and Psoriatic Arthritis in Adults

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Comparative Effectiveness of Drug Therapy for Rheumatoid Arthritis and Psoriatic

Arthritis in Adults

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Background

Rheumatoid and psoriatic arthritis are among the most disabling forms of

arthritis. Rheumatoid arthritis (RA), which affects 1 percent of the U.S. adult

population (or upwards of 2 million individuals), is an autoimmune disease that

involves inflammation of the synovium (a thin layer of tissue lining a

joint space) with progressive erosion of bone, leading in most cases to

misalignment of the joint, loss of function, and disability. The disease tends

to affect the small joints of the hands and feet in a symmetric pattern, but

other joint patterns are often seen. The diagnosis is based primarily on the

clinical history and physical examination. Psoriatic arthritis (PsA) affects

fewer people than RA (approximately 1 million people in the United States).

PsA is associated with the skin disease psoriasis. It has a highly

variable

presentation, which generally involves pain and inflammation in joints and

progressive joint involvement and damage. Like RA, PsA can be disabling.

Treatment of patients with RA and PsA aims to control pain and inflammation and,

ultimately, to slow the progression of joint destruction and disability.

Available therapies for RA include corticosteroids; synthetic disease-modifying

antirheumatic drugs, or DMARDs (hydroxychloroquine, leflunomide, methotrexate,

and sulfasalazine); and biologic DMARDs (abatacept, adalimumab, anakinra,

etanercept, infliximab, rituximab). Three biologics (adalimumab, etanercept,

and infliximab) are also classified as anti-tumor necrosis factor (anti-TNF)

drugs.

Experts have not arrived at a consensus about the comparative

efficacy

of different types of combination therapy—synthetic DMARDs, synthetic DMARDs

with corticosteroids, or synthetic DMARDs with biologic DMARDs—all often in

combination with the synthetic DMARD methotrexate. In addition, there is debate

about how early in the disease process combination therapy should be initiated

and whether patients will respond to a biologic agent if they have previously

failed a different biologic agent. Many questions remain about the risks

of these agents across a spectrum of adverse events from relatively minor side

effects, such as injection site reactions, to severe and possibly

lifethreatening

problems, such as severe infections or infusion reactions. Finally, very little

is known about the benefits or risks of these drugs in different

patient

subgroups, including ethnic minorities, the elderly, pregnant women, and

patients with other comorbidities.

Historically, few trials have been conducted on patients with PsA, with only

minimal research conducted before biologic agents were introduced; management

options tended to be adapted from RA trial evidence. All the same issues noted

for RA of short- and long-term risks and safety, as well as performance

in population subgroups, have been only minimally addressed to date for PsA.

This report from the RTI-University of North Carolina Evidence-based Practice

Center summarizes the evidence on the comparative efficacy, effectiveness,

and harms of corticosteroids, synthetic DMARDs, and biologic DMARDs in the

treatment of patients with either RA or PsA. The key questions (KQs) were

developed

through a public process in conjunction with the Scientific Resource Center at

the Oregon Health and Science University. The KQs are as follows:

KQ 1. For patients with rheumatoid arthritis or psoriatic arthritis, do

drug

therapies differ in their ability to reduce patient-reported symptoms, to slow

or limit progression of radiographic joint damage, or to maintain remission?

KQ 2. For patients with rheumatoid arthritis or psoriatic arthritis, do

drug

therapies differ in their ability to improve functional capacity or quality of

life?

KQ 3. For patients with rheumatoid arthritis or psoriatic arthritis, do

drug

therapies differ in harms, tolerability, adherence, or adverse effects?

KQ 4. What are the comparative benefits and harms of

drug

therapies for rheumatoid arthritis and psoriatic arthritis in subgroups of

patients based on stage of disease, history of prior therapy, demographics,

concomitant

therapies, or comorbidities?

We identified 2,153 citations from our searches. Working from 619 articles

retrieved for full review, we included 156 published articles reporting on 103

studies: 22 head-to-head randomized controlled trials (RCTs), 1 head-to-head

nonrandomized controlled trial, 13 placebo-controlled trials, 10 meta-analyses

or systematic reviews, 55 observational studies, and 2 poor-quality pooled

data

analyses on subgroups. Of the 103 included studies, 51 (50 percent) were

supported by pharmaceutical companies, 21 (20 percent) were funded by

governmental

or independent funds, and 11 (11 percent) were supported by a combination of

pharmaceutical and government funding. We could not determine the source of

support for 20 studies (19 percent). One-quarter of the individual trials were

rated good quality; most were found to be fair quality.

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Conclusions

We present our major findings in this section by type of

drug

comparison and important outcomes (both benefits and harms).

Summary Table A

summarizes the information for RA. We limit our findings in the Executive

Summary to RA because no comparative evidence exists on PsA for any drugs. We

also have not presented findings from subpopulation analyses for RA because the

strength of evidence for age, sex, and comorbidities is very weak.

Monotherapy vs. Monotherapy

Synthetic DMARDs. The

data

show no differences in radiographic outcomes over 2 years for leflunomide and

methotrexate. One

systematic review

that included a

meta-analysis

of two RCTs suggested that higher proportions of patients on methotrexate than

on leflunomide met the American College of Rheumatology (ACR) 20-percent

improvement criteria at 1 year (

odds ratio

[OR], 1.43; 95-percent

confidence interval

[CI], 1.15-1.77, P = 0.001), but

statistical significance

was lost at 2 years (OR, 1.28; 95-percent CI, 0.98-1.67). However, patients on

methotrexate had less improvement in functional status and health-related

quality of life than patients taking leflunomide (Short Form [sF]-36 physical

component: 4.6 vs. 7.6, P < 0.01; Health Assessment Questionnaire Disability

Index [HAQ-DI]: -0.26 vs. -0.45, P < 0.01). Existing head-to-head evidence

(three RCTs) supports no differences in

efficacy

between methotrexate and sulfasalazine by ACR 20, disease activity score (DAS),

and functional capacity.

For leflunomide vs. sulfasalazine,

data

are limited to one RCT with 2-year followup that reported that leflunomide

resulted in a higher proportion of patients reaching ACR 20-percent improvement

and ACR 50-percent improvement criteria and greater improvement in functional

capacity (ACR 20: 82 percent vs. 60 percent, P < 0.01; ACR 50: 52 percent

vs. 25 percent, P < 0.01; HAQ: -0.50 vs. -0.29, P < 0.03). Radiographic changes

were not different for those treated with leflunomide and those treated

with sulfasalazine.

No differences in tolerability were reported for leflunomide, methotrexate, and

sulfasalazine in three

efficacy

trials and one

meta-analysis

of

data

up to 3 years. Similarly, discontinuation rates because of adverse events did

not differ among leflunomide, methotrexate, or sulfasalazine. In the

meta-analysis,

2-year withdrawals attributed to adverse events were not significantly different

for leflunomide vs. methotrexate (

relative risk

[RR], 1.19; 95-percent CI, 0.89-1.6) or sulfasalazine (RR, 0.77; 95-percent CI,

0.45-1.33). However, in one

meta-analysis

of 71 RCTs and 88 observational studies, at 5 years the proportion of patients

who were continuing to take methotrexate was higher than the proportion

continuing

to take sulfasalazine (36 percent vs. 22 percent, P = not reported [NR]).

Biologic DMARDs. We did not find any head-to-head RCTs that compared one

biologic DMARD with another. No evidence exists on abatacept and rituximab

compared

with other biologic DMARDs.

Existing direct head-to-head evidence is limited to one nonrandomized,

open-label

effectiveness

trial and two prospective

cohort

studies comparing etanercept with infliximab. In all three studies, patients on

etanercept had a faster onset of action than patients on infliximab, although

no differences in

effectiveness

were apparent between the two agents. The above findings are generally

consistent with results from three adjusted indirect comparison models

(adalimumab,

etanercept, and infliximab) that reported no differences in

efficacy

among anti-TNF drugs.

Adjusted indirect comparisons also indicated that anakinra has lower

efficacy

than anti-TNF drugs. Although not all results reached statistical significance,

anakinra had consistently lower response rates on ACR 20 (RR, 1.64; 95-percent

CI, 1.04-2.56) and ACR 50 (RR, 1.89; 95-percent CI, 0.98-3.57) than anti-TNF

drugs as a class.

Biologic DMARDs vs. biologic DMARDs. Biologic DMARDs were generally well

tolerated in

efficacy

studies. Long-term extension studies of anti-TNF drugs indicated that the rate

of adverse events does not increase over time. One nonrandomized, open-label

trial directly compared the tolerability of two biologic DMARDs. This 12-month

study

did not report any differences in harms between etanercept and infliximab.

A good-quality

systematic review

reported that the mean crude incidence rates of injection site reactions in RCTs

and observational studies were substantially higher in patients using anakinra

(67.2 percent; 95-percent CI, 38.7-95.7) than in patients on adalimumab (17.5

percent; 95-percent CI, 7.1-27.9) or etanercept (22.4 percent; 95-percent

CI, 8.5-36.3).

Otherwise, evidence from placebo-controlled trials and observational studies is

insufficient to draw conclusions about the comparative tolerability and

safety of biologic DMARDs. One prospective

cohort

study

suggested that adalimumab, etanercept, and infliximab did not differ in the

risk

for serious infections. Three fair-quality observational studies, however,

indicated that infliximab might have a higher

risk

of granulomatous infections than etanercept.

The evidence on comparative discontinuation rates is limited to three

observational studies. In one large, retrospective

cohort

study, anakinra led to statistically significantly higher overall

discontinuation rates (41 percent) than either etanercept (31 percent; P =

0.004) or infliximab

(35 percent; P = 0.03).

Biologic DMARD vs. synthetic DMARD. Three RCTs compared the

efficacy

of two anti-TNF drugs (adalimumab or etanercept) with that of methotrexate. Two

trials enrolled exclusively methotrexate-naive patients with early RA; the

third trial included a mixed population of methotrexate-naive patients and

patients who had failed synthetic DMARDs other than methotrexate. In all three

studies, results did not indicate substantial differences in clinical response,

functional capacity, or quality of life between either adalimumab or etanercept

and methotrexate. In the adalimumab study, 25 percent of patients achieved

remission in each treatment group. Radiographic outcomes, however, were

statistically

significantly better in patients treated with biologic DMARDs than in those

tapered with methotrexate. For example, in the ERA (Early Rheumatoid Arthritis)

study, 72 percent of patients on etanercept and 60 percent of patients on

methotrexate had no radiographic progression of the disease (P = 0.007). What

implications such intermediate outcomes have on the long-term progression of the

disease remains unclear. No studies comparing biologics with synthetic

DMARDs other than methotrexate were available.

One prospective

cohort

study

enrolled a population who failed initial RA treatment. After 12 months, patients

on biologic DMARDs as a class had almost four times higher odds of achieving

functional independence (OR, 3.88; 95-percent CI, 1.71-8.79) and almost two

times higher odds of achieving remission (OR, 1.95; 95-percent CI, 1.20-3.19)

than patients on synthetic DMARDs. In both groups, only half of patients who

were in remission at 6 months achieved a sustained remission until 12 months.

In general, adverse events did not differ significantly between biologic and

synthetic DMARDs. Studies were too small to assess reliably differences in

rare but severe adverse events.

Combination Therapy vs. Monotherapy

Synthetic DMARDs. The

data

are limited by the number of supporting studies for each

drug

combination.

Sulfasalzine-methotrexate vs. monotherapy. In two trials lasting 4 years, ACR

response rates and radiographic changes did not differ in patients with early

RA. Findings of these studies are consistent and do not support a difference in

functional capacity between combination therapy and monotherapy. One

study

in patients with early RA, however, reported improved DAS scores at 18 months

with combination therapy (DAS score -0.67 combination, -0.30 sulfasalazine,

-0.26 methotrexate; P = 0.023 for combination vs. methotrexate).

Synthetic DMARD-corticosteroid vs. monotherapy. Three RCTs examined combination

strategies of one or more synthetic DMARDs with corticosteroids against

synthetic DMARD monotherapy. These trials suggest better outcomes with the

combination strategies, although each

study

used different

outcome

measures, including ACR, DAS, and radiographic scores. One RCT comparing a

combination involving a synthetic DMARD (either methotrexate or sulfasalazine)

and a corticosteroid with a synthetic DMARD monotherapy had a higher remission

rate in the combination group than in the monotherapy group (remission defined

by DAS 28 < 2.6: 55.5 percent vs. 43.8 percent; P = 0.0005). Patients with early

RA had significantly lower radiographic progression and fewer eroded joints

with the combination treatment than with monotherapy.

One open-label RCT compared synthetic DMARD use with and without prednisolone.

It was found that the prednisolone group had a greater improvement in functional

capacity. The investigators did not compare the results statistically, and the

clinical relevance of the results is uncertain.

Combination studies involving two synthetic DMARDs, including sulfasalazine and

methotrexate, vs. one DMARD showed no differences in withdrawal rates because

of adverse events. Combination studies including prednisone with one or more

DMARDs also had no differences in discontinuation rates between groups.

Biologic DMARDs. The

data

are limited by the number of supporting studies for each

drug

combination.

Biologic combination vs. monotherapy. One RCT did not detect any synergistic

effects of a combination treatment of etanercept and anakinra compared with

etanercept monotherapy. The incidence of serious adverse events, however, was

substantially higher with the combination treatment (14.8 percent vs. 2.5

percent; P = NR).

Two trials indicated that a combination treatment of two biologic DMARDs can

lead to substantially higher rates of severe adverse events than biologic DMARD

monotherapy. The evidence, however, is limited to combinations of anakinra plus

etanercept and abatacept plus anakinra, adalimumab, etanercept, or infliximab.

Biologic combination with methotrexate vs. biologic DMARDs alone. Most of the

other studies compared combinations of biologic DMARDs and methotrexate with

monotherapies of these drugs. Overall, combination therapy of biologic DMARDs

and methotrexate achieved better clinical response rates than monotherapies.

For example, four RCTs and two prospective

cohort

studies suggested that a combination of adalimumab, etanercept, infliximab, or

rituximab with methotrexate leads to statistically significantly greater

improvements than monotherapy of biologic DMARDs. In one trial, significantly

more patients on the combination therapy (adalimumab plus methotrexate) than

patients on adalimumab monotherapy (59 percent vs. 37 percent; P < 0.001)

exhibited responses on the ACR 50 after 2 years of treatment. Likewise, more

patients on etanercept plus methotrexate than on etanercept monotherapy achieved

remission (DAS < 1.6; 35 percent vs. 16 percent; P < 0.0001) during the

TEMPO (Trial of Etanercept and Methotrexate with Radiographic

Patient

Outcomes) study. Both RCTs suggested that a combination of either adalimumab or

etanercept with methotrexate led to statistically significantly greater

improvements in functional capacity or health-related quality of life than

monotherapy with a biologic DMARD. In methotrexate-naive patients with early,

aggressive RA, better ACR 50 response, significantly greater clinical remission,

and less radiographic progression were seen in the combination therapy

group.

Biologic DMARD combinations with other synthetics vs. biologic DMARDs. Only one

study

used sulfasalazine as a synthetic DMARD in combination with a biologic DMARD. A

combination of etanercept with sulfasalazine did not achieve better outcomes

than etanercept monotherapy. No differences in adverse events were found between

combinations of biologic and synthetic DMARDs and biologic DMARD monotherapy.

Biologic DMARD combinations with methotrexate vs. methotrexate alone. Two trials

found that a combination of either adalimumab plus methotrexate or infliximab

plus methotrexate in patients with early, aggressive RA who were methotrexate

naive led to better clinical and radiographic outcomes than methotrexate

monotherapy. After 2 years of treatment, 59 percent of patients on adalimumab

plus methotrexate met ACR 50 criteria, compared with 43 percent of patients

on methotrexate monotherapy (P < 0.001). Likewise, significantly more patients

in the infliximab plus methotrexate combination groups than in the methotrexate

group exhibited remission rates in the ASPIRE (Active controlled

Study

of Patients receiving Infliximab for Rheumatoid arthritis of Early onset)

retrial. Both RCTs and one prospective

cohort

study

found greater improvements in functional capacity and quality of life with

combination therapies (adalimumab, infliximab, or etanercept plus methotrexate)

than with methotrexate alone.

In general, no statistically significant differences in adverse events existed

between combinations of biologic and synthetic DMARDs and synthetic DMARD

monotherapy. Studies, however, were too small to assess reliably differences in

rare but severe adverse events. An exception was a

study

with high-dose infliximab plus methotrexate therapy, which led to a

statistically significantly higher rate of serious infections than methotrexate

monotherapy.

Combination Therapy Comparisons or Other Treatment Strategies

Evidence is insufficient to draw firm conclusions about whether one combination

strategy is better than any other. Two RCTs reported more improved response

rates at 2 years for the combination of sulfasalazine, methotrexate, and

hydroxychloroquine than for one or two drugs in patients who had previously been

on monotherapy. ACR 20 response rates were 78 percent for triple therapy, as

contrasted with 60 percent for methotrexate and hydroxychloroquine (P = 0.05)

and 49 percent for methotrexate and sulfasalazine (P = 0.002). Groups did not

differ in withdrawal rates.

In patients with early RA,

data

are limited to one

effectiveness

trial. It reported less radiographic progression over 12 months with either (1)

metho-trexate, sulfasalazine, and high-dose tapered prednisone or (2)

methotrexate

and infliximab vs. (3) sequential DMARD therapy or (4) step-up combination

therapy (median modified Sharp/van der Heijde score change: 2.0, 2.5, 1.0, and

0.5, respectively; P = 0.003 for group 1 vs. group 3, P < 0.001 for group 1 vs.

group 4, P = 0.007 for group 2 vs. group 3, P < 0.001 for group 2 vs. group

4). Patients treated with initial combination therapy of methotrexate,

sulfasalazine, and tapered high-dose prednisone or initial combination therapy

with

infliximab and methotrexate had statistically significantly better functional

ability (Dutch version of the HAQ) at 12 months than those treated with

sequential

DMARD therapy starting with methotrexate. The magnitude of difference was small,

however. The groups did not differ in serious adverse events.

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Remaining Issues

Most of the trials were conducted in RA patients;

data

are limited for PsA patients. Common problems for both RA and PsA include the

lack of

effectiveness

informationÑi.e., studies and findings with a high level of applicability to

community populations. Future investigations need to take into account factors

such as varying adherence because of administration schedules, costs, and

adverse events. Information about the performance of these drugs in subgroups

of patients defined by health status, sociodemographics, or other variables is

also needed.

To address problems with current literature, future studies should use designs

of longer duration and followup, enroll patients representing key subgroups

(or report on them when they are enrolled), and ensure that quality of life (or

other patient-oriented outcomes) is measured in addition to clinician-oriented

measures, such as joint erosion.

The gaps in information for specific RA therapies are substantial. With respect

to comparative efficacy, future studies should focus on head-to-head trials

assessing combination therapies involving synthetic DMARDs in comparison with

those involving biologic DMARDs. Adequately powered, long-term RCTs must

also examine different treatment strategies with and without corticosteroids,

synthetic DMARDs, and biologic DMARDs to determine the best therapy to prevent

or minimize debilitating joint damage in patients with RA. Additionally, no

head-to-head RCTs have compared one biologic DMARD with another; this is a

significant hole in the literature that future research should fill. However,

this is less likely to occur because of the expense of biologic DMARDs.

Investigators

may find large registries helpful in identifying the same kinds of patients

treated with different agents.

With respect to

study

design, studies of longer duration and followup will be beneficial, given that

RA is a progressive, chronic condition. Such studies will also help to clarify

whether early initiation of any regimen can improve the long-term

prognosis

of RA and, particularly, whether early use of biologic DMARDs is beneficial.

Minimal research was conducted on PsA before biologic DMARDs were introduced, so

the gaps in this knowledge base are larger than those in RA. Going forward,

head-to-head comparisons of any of the

drug

therapies to treat PsA are needed, probably with particular attention to

biologic DMARDs. Issues similar to those for RA with respect to long-term

outcomes

and early initiation are also important for PsA.

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Addendum

We updated our literature search in September 2007 and identified 243 new

citations. We obtained the full text for 22 references and included 16 published

articles on 10 new studies. We report relevant new

data

below but, overall, these studies do not change the conclusions of this report.

Rheumatoid Arthritis

Biologic comparisons. We found eight new studies on biologics that met our

eligibility criteria;1-8 five of these were observational studies assessing the

safety of biologics.4-8 Overall, these studies did not change our conclusions or

any ratings of the strength of the evidence. Nevertheless, some studies

added notable new evidence.

For example, one RCT compared the

efficacy

of rituximab monotherapy with a combination treatment of rituximab and

methotrexate in patients with active RA despite ongoing methotrexate treatment.3

To date, this is the first

study

comparing these treatment strategies. Results are similar to trials comparing

adalimumab or etanercept monotherapies with combinations of these biologics

and methotrexate. During the entire followup and after 2 years, the combination

group experienced substantially greater response rates than the rituximab

monotherapy group (ACR 50 at 2 years: 20 percent vs. 8 percent).

A prospective, population-based

cohort

study

from Sweden, enrolling more than 1,100 patients, reported statistically

significantly higher adherence rates for patients on etanercept and methotrexate

than for those on infliximab and methotrexate.1 After 5 years of treatment, 65

percent of patients on etanercept and 36 percent of patients on infliximab

still adhered to therapy. Infliximab led to statistically significantly more

withdrawals owing to adverse events than etanercept (

data

not reported; P < 0.001). To date, this

study

is the longest comparative assessment of two biologic treatments for RA.

Combination strategy comparisons. We found two articles9,10 containing 2-year

followup

data

for a previously reported RCT comparing complex combination strategies.11 The

2-year

data

reinforce our conclusions that patients on initial combination therapy of

methotrexate, sulfasalazine, and tapered high-dose prednisone or initial

combination

therapy with methotrexate and infliximab had less radiographic progression than

sequential monotherapy and step-up combination therapy (median increase

in total Sharp/van der Heijde score: 1.0, 1.0, 2.0, and 2.0, respectively).

However, all arms had similar disease activity by disease activity score (DAS)

values at 2 years regardless of which initial therapy they had received.

Psoriatic Arthritis

We identified six new articles published on studies concerning the treatment of

PsA.12-17 Two were new, formerly unreported studies;12,13 four of the articles

contained additional outcomes on studies previously reported.14-17 Overall,

these studies did not change our conclusions or any ratings of the strength

of the evidence.

However, one of the studies added new evidence by comparing biologics with

methotrexate, the conventional treatment of PsA.12 In this prospectively planned

observational

study

in Norway, 6 months of treatment with biologics and biologics plus methotrexate

vs. methotrexate alone were compared in 1,022 patients. The group treated

with biologics had poorer baseline characteristics than the methotrexate group;

once statistical adjustments were made, the differences at 6 months were

significantly in favor of the biologics group for the DAS-28 (P < 0.001) and

other measures.

Addendum References

List of 17 items

1. sen LE, Saxne T, Nilsson JA, Geborek P. Impact of concomitant DMARD

therapy on adherence to treatment with etanercept and infliximab in rheumatoid

arthritis. Results from a six-year observational

study

in southern Sweden. Arthritis Res Ther. 2006;8(6):R174.

2. Weinblatt M, Schiff M, Goldman A, Kremer J, Luggen M, Li T, et al. Selective

costimulation modulation using abatacept in patients with active rheumatoid

arthritis while receiving etanercept: a randomised clinical trial. Ann Rheum

Dis. 2007(2):228-34.

3. Strand V, Balbir-Gurman A, Pavelka K, Emery P, Li N, Yin M, et al. Sustained

benefit in rheumatoid arthritis following one course of rituximab: improvements

in physical function over 2 years. Rheumatology (Oxford). 2006

Dec;45(12):1505-13.

4. Burmester GR, Mariette X, Montecucco C, Monteagudo-Saez I, Malaise M,

Tzioufas AG, et al. Adalimumab alone and in combination with disease-modifying

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5. den Broeder AA, Creemers MC, Fransen J, de Jong E, de Rooij DJ, Wymenga A,

et al.

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6. Curtis JR, Patkar N, Xie A, C, JJ, Saag M, et al.

Risk

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7. Schneeweiss S, Setoguchi S, Weinblatt ME, Katz JN, Avorn J, Sax PE, et al.

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risk

of serious bacterial infections in elderly patients with rheumatoid arthritis.

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8. Ruyssen-Witrand A, Gossec L, Salliot C, Luc M, Duclos M, Guignard S, et al.

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9. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D,

Kerstens PJ, Hazes JM, et al. Comparison of treatment strategies in early

rheumatoid

arthritis: a randomized trial. Ann Intern Med. 2007 Mar 20;146(6):406-15.

10. Allaart CF, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Breedveld FC,

Dijkmans BA. Aiming at low disease activity in rheumatoid arthritis with initial

combination therapy or initial monotherapy strategies: the BeSt study. Clin Exp

Rheumatol. 2006 Nov-Dec;24(6 Suppl 43):S-77-82.

11. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D,

Kerstens PJ, Hazes JM, et al. Clinical and radiographic outcomes of four

different

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study): a randomized, controlled trial. Arthritis Rheum. 2005

Nov;52(11):3381-90.

12. Heiberg MS, Kaufmann C, Rodevand E, Mikkelsen K, Koldingsnes W, Mowinckel

P, et al. The comparative

effectiveness

of anti-TNF therapy and methotrexate in patients with psoriatic arthritis: 6

month results from a longitudinal, observational, multicentre study. Ann Rheum

Dis. 2007 Aug;66(8):1038-42.

13. Genovese MC, Mease PJ, Thomson GT, Kivitz AJ, Perdok RJ, Weinberg MA, et

al. Safety and

efficacy

of adalimumab in treatment of patients with psoriatic arthritis who had failed

disease modifying antirheumatic

drug

therapy. J Rheumatol. 2007 May;34(5):1040-50.

14. van der Heijde D, Kavanaugh A, Gladman DD, Antoni C, Krueger GG, Guzzo C,

et al. Infliximab inhibits progression of radiographic damage in patients

with active psoriatic arthritis through one year of treatment: Results from the

induction and maintenance psoriatic arthritis

clinical trial

2. Arthritis Rheum. 2007 Aug;56(8):2698-707.

15. Kavanaugh A, Krueger GG, Beutler A, Guzzo C, Zhou B, Dooley LT, et al.

Infliximab maintains a high degree of clinical response in patients with active

psoriatic arthritis through 1 year of treatment: results from the IMPACT 2

trial. Ann Rheum Dis. 2007 Apr;66(4):498-505.

16. Gladman DD, Mease PJ, Ritchlin CT, Choy EH, Sharp JT, Ory PA, et al.

Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week

data

from the Adalimumab

Effectiveness

in Psoriatic Arthritis Trial. Arthritis Rheum. 2007 Feb;56(2):476-88.

17. Gladman DD, Mease PJ, Cifaldi MA, Perdok RJ, Sasso E, Medich J. Adalimumab

improves joint-related and skin-related functional impairment in patients

with psoriatic arthritis: patient-reported outcomes of the Adalimumab

Effectiveness

in Psoriatic Arthritis Trial. Ann Rheum Dis. 2007 Feb;66(2):163-8.

list end

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Full Report

This executive summary is part of the following document: Donahue KE, Gartlehner

G, Jonas DE, Lux LJ, Thieda P, Jonas B, Hansen RA, LC,

SC, Lohr KN.

Comparative

Effectiveness

of

Drug

Therapy for Rheumatoid Arthritis and Psoriatic Arthritis in Adults. Comparative

Effectiveness

Review No. 11. (Prepared by RTI-University of North Carolina Evidence-based

Practice Center under Contract No. 290-02-0016.) Rockville, MD: Agency for

Healthcare

Research and Quality. November 2007.

Back to top

For Print Copies

For more copies of Comparative

Effectiveness

of

Drug

Therapy for Rheumatoid Arthritis and Psoriatic Arthritis in Adults: Executive

Summary. No. 11 (AHRQ Pub. No. 08-EHC004-1), please call the AHRQ Clearinghouse

at 1-800-358-9295 or e-mail

ahrqpubs@....

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Table

Table with 3 columns and 26 rows

Abbreviations: ACR = American College of Rheumatology; DMARD = disease-modifying

antirheumatic drug; HAQ-DI = Health Assessment Questionnaire Disability

Index; RA = rheumatoid arthritis; SF-36 = Medical Outcomes

Study

Short Form 36; TNF = tumor necrosis factor.

Summary Table A. Summary of findings: rheumatoid arthritis

Key comparisons

Efficacy

and strength of evidence

Harms and strength of evidence

Monotherapy vs. Monotherapy

Synthetic DMARDs

Leflunomide vs. methotrexate

No differences in ACR 20 or radiographic responses:

Moderate

Greater improvement in functional status (HAQ-DI) and health-related quality of

life (SF-36 physical component) for leflunomide:

Moderate

No differences in work productivity outcomes:

Moderate

No differences in tolerability and discontinuation rates:

Moderate

Leflunomide vs. sulfasalazine

Higher ACR 20 and ACR 50 response rates and greater improvement in functional

capacity for leflunomide:

Low

No differences in radiographic changes:

Low

No differences in tolerability and discontinuation rates:

Moderate

Sulfasalazine vs. methotrexate

No differences in ACR 20 response, disease activity scores, functional capacity,

and radiographic changes:

Moderate

No differences in tolerability; more patients on methotrexate than sulfasalazine

long term:

Moderate

Biologic DMARDs

Biologic DMARDs vs. biologic DMARDs

Anti-TNF drugs (adalimumab, etanercept, infliximab) vs. anti-TNF drugs

No differences in ACR 20/50 response rates among anti-TNF drugs:

Moderate

Insufficient evidence on the comparative

risk

of harms:

Low

Biologic DMARDs vs. biologic DMARDs

Indirect comparisons consistently showed anakinra to have lower ACR 20 and ACR

50 response rates than anti-TNF drugs as a class:

Moderate

Risk

for injection site reactions apparently higher for anakinra than for adalimumab

and etanercept:

Moderate

Biologic DMARDs vs. synthetic DMARDs

Anti-TNF drugs vs. methotrexate

In patients with early RA, no differences in clinical response, functional

capacity, and quality of life between adalimumab or etanercept and methotrexate;

better radiographic outcomes in patients on biologic DMARDs than in patients on

synthetic DMARDs:

Moderate

In patients who had failed initial RA treatment, greater functional independence

and remission for anti-TNF drugs as a class than synthetic DMARDs as a

class:

Moderate

No differences in adverse events in

efficacy

studies:

Low

Insufficient evidence on differences in the

risk

for rare but severe adverse events:

Low

Combination Therapy vs. Monotherapy

Synthetic DMARDs vs. Synthetic DMARDs

Sulfasalazine plus methotrexate vs. monotherapy

In patients with early RA, no differences in ACR 20 response rates or

radiographic changes:

Moderate

No differences in functional capacity in all patients:

Moderate

In patients with early RA, significantly better disease activity scores with

combination therapy:

Low

No differences in withdrawal rates attributable to adverse events:

Moderate

1, 2, or 3 synthetic DMARDs (methotrexate, sulfasalazine, hydroxychloroquine)

plus prednisone vs. 1 synthetic DMARD

In patients on 1, 2, or 3 synthetic DMARDs plus prednisone, improved ACR 50

response rates, disease activity scores, and less radiographic progression:

Moderate

In patients with early RA, significantly lower radiographic progression and

fewer eroded joints:

Low

Better outcomes with the combination strategies for functional capacity:

Low for each individual comparison,

Moderate for combination therapy vs. monotherapy

No differences in discontinuation rates:

Moderate

Biologic DMARD Combinations

Biologic DMARD plus biologic DMARD vs. biologic DMARD

No additional treatment effects from combination of etanercept plus anakinra

compared with etanercept monotherapy:

Low

Substantially higher rates of serious adverse events from combination of two

biological DMARDs than from monotherapy

Moderate

Biologic DMARD plus methotrexate vs. biologic DMARD

Better clinical response rates, functional capacity, and quality of life from

combination therapy of biologic DMARD plus methotrexate than from monotherapy

with biologics:

Moderate

In methotrexate-naive patients with early aggressive RA, better ACR 50 response,

significantly greater clinical remission, and less radiographic progression

in thecombination therapy group:

Low

No differences in adverse events in

efficacy

studies:

Low

Insufficient evidence on differences in the

risk

for rare but severe adverse events:

Low

Biologic DMARDs plus synthetic DMARD other than methotrexate vs. biologic DMARD

No difference in clinical response rates, functional capacity, and quality of

life between etanercept plus sulfasalazine and etanercept monotherapy:

Low

No differences in adverse events in

efficacy

studies:

Low

Insufficient evidence on differences in the

risk

for rare but severe adverse events:

Low

Biologic DMARDs plus methotrexate vs. methotrexate

Better clinical response rates, functional capacity, and quality of life from

combination therapy of biologic DMARDs and methotrexate than from methotrexate

monotherapy:

Moderate

No differences in adverse events in

efficacy

studies:

Low

Insufficient evidence to make conclusion on differences in the

risk

for rare but severe adverse events:

Low

Combination Therapy vs. Combination Therapy or Other Treatment Strategy

Sulfasalazine plus methotrexate plus hydroxychloroquine vs. 2 drugs

In patients previously on monotherapy, higher ACR 20/50 response rates for

triple therapy than for 2-

drug

combinations:

Moderate

In patients with no previous use of

study

drugs, higher ACR 20/50 response rates in the triple combination therapy group

than in methotrexate plus sulfasalazine or methotrexate plus hydroxychloroquine:

Low

No differences in withdrawal rates attributable to adverse events:

Moderate

Sequential monotherapy starting with methotrexate vs. step-up combination

therapy vs. combination with tapered high-dose prednisone vs. combination with

infliximab

Less radiographic progression, lower disease activity scores, and better

functional ability from initial combination therapy of methotrexate,

sulfasalazine,

and tapered high-dose prednisone or initial combination therapy with infliximab

plus methotrexate than from sequential DMARD monotherapy or step-up combination

therapy:

Low

No differences in serious adverse events between groups:

Low

table end

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